Hydrazine derivatives



1 benzen- Patented Jan. 15, 1963 3,673,819 HYDRAZlNL'J DERIVATHVES OttoStraub, Bottmingen, and Paul Zeiier, Nenallsehwil, Switzerland,assignors to Hofimann-La Roche Inc Nutley, N.li., a corporation of NewJersey No Drawing. Filed Apr. 29, 1960, Ser. No. 23,369

Claims priority, application Switzerland Apr. 39, 1959 8 filaims. (Cl.EMF-249) This invention relates to hydrazine derivatives. Moreparticularly, the invention relates to hydrazine derivatives having thefollowing structural formula:

(I) 2 12 n s R1-NN=on, wherein R represents hydrogen or acyl, R'represents aralkyl, cycloalkyl or alkyl, R represents hydrogen or alkyland R, represents pyridyl,

groups such as benzoyl, phenacetyl and the like, as well as heterocyclicacyl groups, preferably nitrogen, sulfur and oxygen-containing, 5-7membered monoheterocyclic acyl groups such as thenoyl, furoyl,isonicotinoyl, nicotinoyl, picolinoyl, and the like. The acyl groups mayalso contain substituents such as the halogens, hydroxy and up to 4carbon atom alkoxy and alkylmercapto groups. I

R represents e.g. straight or branched chain lower alkyl'grioups such asmethyl, ethyl, propyl, 'isopropyl, butyl,

isobutyl and the like, phenyl loweralkyl groups such as benzyl, and 3 to6 carbon cycioalkyl groups suchas cyclopropyl, cyclobutyhcyclopentylcyclohexyl. R in addition to hydrogen, represents lower alkylgroupssimilar to those represented byR h R represents the 2-,

3a or .4-pyridyl radical.

Representative of the compounds contemplated by invention are thefollowing:

-' l-benzyl-2- 4-pyridyl-methylene) hydrazine1-isopropyl-2(a-4-pyridyl-ethylidene)hydrazine 1-benzyl-2-(a 4pyridylrethylidene)hydrazine I l-benzoyl-l-isopropyl-2-(4-pyridylmethylene)hydrazine ene),-,hydr.azine drazine.v

'1: (2 furoyl)f-1-isopropyl 2 4 pyridyl-methylene)hy- *drazine 1 pchlorohenzoyl-1-isopropyl 2-(3:pyridyl-rnethylene) adyiatyudaa y;

2 1 p chlorobenzoyl-l-benayl-Z-(4-pyridy1-methylene) hydrazine 1pivaloyl l benzyl-Z-(a-4-pyridyl-ethylidene)hydrazine The compoundsdescribed above are produced by condensing a compound of the formula Ila ltl-N-Nrn wherein R has the same significance as above and Rrepresents hydrogen, aralkyl or up to 7 carbon atom aliphatic oralicyclic groups, with a carbonyl compound of the formula wherein R andK, have the same significance as in Formula I.

The resulting hydrazone may, if desired, be acylated when R representshydrogen. If R represents hydrogen, a group represented by R may beintroduced into the hydrazone.

' In the first stage of the process a hydrazine derivative of Formula IIis condensed with an aldehyde or ketone of Formula 111, preferably in aninert solvent such as benzene, ethanoh'water or the like at roomtemperature or above. 1

If a non-acylated compound is obtained in the first stage, the hydrazonemay then be acylated in the second stage by means of an acylating agent.Reactive acid de-. rivativesv such as acid halides, especiallychlorides, esters or anhydrides may be used. I Symmetrical acidanhydride's containing two of the same acyl groups or mixed anhydrides,for example, with lower alkanoic acids or carboxylic acid monoesters,may be used. i

Free acids may also be used as acylating agents, In. I that case, thecondensation is preferably ,efiected in the I presence of an N, N-disubstituted carbodiimide. The carbodiimide may be obtained, forexample, by treating v hexylacrbodiimide, urea derivatives are obtainedasby- 1 (2 thenoyli-1-isopropyl-Z (d pyridyl-methylene)hy-Q 1 representshydrogen is 'used'in 'the first stage, thehy: I r: drazone obtainedjas aresultof the condensation with] f the carbonyl; compoundis treatedwithan agent'supplying ,the group R rfflhe introduction of. this.substituentoc'- curs upon'reaction witha 'halide of theformula 'Rg halin the presenceof an" alkali metal alcoholate, preferably a v Thecompounds of upon reactionwith-inorganic ororganic acids and these saltsare also within thei"'sqpeaof..the invention" PI d CmOnde,hydrobroinide, hydroicdide,".etc.,'-su1fate; nitrate, phosphate andthelike, and organic sal'ts, =e'.g.=' 3 oxalate,:tartrate,citrate et v e'Tl1e,pr'oducts described;

inhibitors. They areluseful ment of depressed ,iorvdistu'rbe'd states.Theyareals'o use;

. accetable acidiadditiorn salt "may" be] 'adrninisteredi in' ten:ventional' dosage forms;'suchiastablets, eli-X fsionhinjectablesandthelike. if

, The following exarnples'are illustrativeof the inventionaTerriperatures:are stated in degrees 'ce'ntigrade'. v

a disubstituted: urea derivative with p-toluenesulfonyl chloride inpyridine. In the condensation reaction the correspondingurea derivativesare reformed. By using-' preferred substituted carbodiirnides, cg. N,N-dicycloi products which are readily separated from the desired reactionproduct. thereactionmay beeffected [at ate perature within the rangeof 0to 50F. C.,-ppreferably at 1. room temperature or slightly abpve.-.

When a starting material of Formula wh r i 5,

sodium-ethoir ide, 1 Formula lqform acid addition salts ire saltsinclude mineraliacidgsalts, .e.g. hydr'ohalid iie aremonoaminefoiridase' i in psychotherapy for treat fill incaseslofcachexia. The base or: pharmaceuticall sus en Example 1 5.54 g.of 1-benzoyl-1-isopropylhydrazine were suspended in 15 ml. of 50%aqueous ethanol and treated with a solution of 3.53 g. 4-pyridinealdehyde in 20 ml. of 50% ethanol. The suspension was heated slowly at atemperature slightly under the boiling point, then permitted to cool.After 24 hours, 100 ml. of water were added to the reaction mixture. Theaqueous solution was extracted with ether, the ether solution was dried,concentrated, and the residue was crystallized from watermethanol (1:1).The l-benzoyl-1-isopropyl-2-(4-pyridylmethyleue)hydrazine melted at73-75.

The starting material, l-benzoyl-l-isopropylhydrazine, was prepared asfollows:

To a solution of 65.6 g. of anhydrous sodium acetate in 1 liter of 50%aqueous ethanol were added 88 g. of isopropylhydrazine hydrochloride andthen 84.8 g. of benzaldehyde. The solution which was clear at first soonbecame turbid. The reaction mixture was agitated for 1 hour, and afterstanding for a short period of time was then extracted with ether. Theether extract was washed with sodium bicarbonate solution and withwater, then dried and concentrated. The oily residue was distilled underhigh vacuum to obtain 1-isopropyl-Z-benzylidenehydrazine, B.P.80-84/0.07 mm.

A solution or 14 g. of benzoyl chloride in 25 ml. of absolute benzenewas dropped into a solution containing 16.2 g. of1-isopropyl-2-benzylidenehydrazine in 100 ml. of absolute benzene and 50ml. of absolute pyridine with the exclusion of moisture. The mixture washeated at 80 for about 2 hours and then concentrated at a temperature ofabout 40 and a pressure of about 15 mm. The residue was digested with alarge quantity of water and the partially solidified product was driedon clay.

The product, l-benzoyl-1-isopropyl-2-benzylidenehydrazine, wascrystallized from methanol-water (2:1), M.P. 75.5-77".

A suspension of 53.2 g. of 1-benzoyl-l-isopropyl-Z-benzylidenehydrazinein 300 ml. of water, 100 ml. of ethanol and ml. of glacial acetic acidand 12 g. of 80% hydrazine hydrate were boiled under reflux for 60hours, then cooledwith ice and finally treated with 67 ml. of 3 Nhydrochloric acid. The precipitated benzalazine was filtered off undersuction. The aqueous filtrate was then treated with 50 ml. ofconcentrated ammonia solution. This was thenconcentrated under watervacuum at 40- 50 and the residue was taken up in chloroform. Theresulting suspension was dried with sodium sulfate, filtered, and thefiltrate was evaporated to dryness. The residue was dried over sulfuricacid for 24 hours in vacuo and crystallized from low boiling petroleumether to obtain l-benzoyl l-isopropylhydrazine, M.P.. 5658.

Example 2 V A solution of 82 g. of anhydrous acetate in 220 ml. of waterwas added to a solution of 110.5 g. of-isopropylhydrazine hydrochloridein 150 ml. of water.- 101.7 g. of 4-pyridine aldehyde 'were addeddropwise, After stirring for 4 hours at a moderately elevatedtemperature, the mixture was permitted to stand for several hours andthen extracted with ether. The ether extract was washed withsodiumbicarbonate and sodium chloride solution, dried and concentrated. Theresidue was purified by distillation under a high vacuum to obtain1-isopropyl-2-(4- pyridylmethylene)hydrazine, B.P. l'10-l13/0.1 mm.,M.P. 61-65";

To a solution of 98 of 1-isopropyl-2-(4-pyridylmethylene) hydrazine in600 ml. of absolute benzene and 300 ml. of absolute pyridine wasaddeddropwise a solution of 84.3 g. of benzoyl chloride in 150 ml. ofabsolute benzene" overa period 'of 1 hour with stirring with theexclusion of moisture.- The mixture was then heated to'boiling for about1 hours. Thepyridine and benzene solvents present were distilled oifunder water vacuum at 40.

The residue was taken up in a large amountjofwater and and p theresulting suspension was thoroughly extracted with ether. The ethersolution was washed with sodium carbonate and sodium chloride solutionsand dried. The ether was then distilled 00?. The residue wascrystallized from water and methanol (2:1) to obtainl-benzoyl-lisopropyl-Z-(4-pyridylmethylene)hydrazine, M.P. 76.5- 77.5.

Example 3 1 isopropyl 2 (4 pyridylmethylene)hydrazine was treated withacetyl chloride according to the procedure described in Example 2 toobtain 1-acetyl-l-isopropyl-2- (4-pyridylmethylene)hydrazine, M.P.92.5-95.5 (crystallized from petroleum ether, boiling range -105 Example4 1 isopropyl 2 (4 pyridylmethylene)hydrazine was acylated withp-chlorobenzoyl chloride according to the procedure described in Example2 to obtain l-(4-chlorobenzoyl) 1isoproyl-2-(4-pyridylrnethylene)hydrazine, M.P. -875 (crystallized frompetroleum ether, boiling range 80-105").

Example 5 1 isopropyl 2 (4 pyridylmethylene)hydrazine was acylated withZ-thenoyl chloride according to the procedure described in Example 2 toobtain 1-(2-thenoy1)-lisopropyl-2-(4-pyridylmethylene)hydrazine whichwas repeatedly precipitated from ethanolwater and then crystallized frompetroleum ether, M.P. 79.581.

Example 6 1 isopropyl 2 (4 pyridylmethylene)hydrazine was acylated withisonicotinoyl chloride hydrochloride by the procedure of Example 2 toobtain 1-isonicotinoyl-1-isopropyl-Z-(4-pyridyl-methylene) hydrazine,M.P. 108- 110 (crystallized from petroleum ether-ethyl acetate, 2: l

Example 7 A solution of 26.1.g. of 2-furoyl chloride in 50 ml. ofabsolute benzene was dropped with stirring and exclusion of moistureinto a solution of 32.6 g. of 1-isopropyl-2-(4-pyridylmethylene)hydrazine in 200 ml. of absolute benzene and ml.of absolute pyridine. The mixture was gently boiled for 1 /2 hours andcencentrated as much as possible at 40 under water vacuum. The residuewas taken up in a small amount of ethanoland stirred with a'large amountof icewater. The precipitate which formed was filtered under suction,dissolved in ethanol and reprecipitated by the addition of water, thenfinally crystallized from water-ethanol (2:1). The 1-2-furoyl)-l-isopropyl-Z-(4-pyridylmethylene)hydrazine melted at 84-85 Example 8 Vthe group consisting of compounds of the formula t it: l a

nr-N- =o-R. wherein R represents a member of the group consist-.

ing of alkanoyl of up to 18 carbon atoms, 4 to7 carbon atomcycloalkanoyl, phenyl lower alkanoyl, thenoyl and furoyl, R representsamember of the group consisting. of lower alkyl, phenyl lower alkyl and3 to 6 carbon c'ycloalkyl, R represents a memconsisting of hydrogen andlower ber of. the group alkyl, and R.; represe uts pyridyl, v

said compounds.

narmaceutically acceptable acid addition salts of 5 O 6 A compound ofthe formula 7. A compound of the formula lower alkyl 0 CFFKOHM Q0ONN=OH-pyridyl o O-NN=OH@ 5 A compound of the formula omoum 8. Acompound of the formula A compound of the formula 10 cfmcfim NRefetences Cited in the file of this patent FOREIGN PATENTS A compoundof the formula 187,112 Austria Oct. 25, 1956 CHwHm a 724,699 GreatBritain Feb. 23, 1955 I 729,348 Great Britain May 4, 1955 729,967 GreatBritain May 11, 1955 A compound of the formula OTHER REFERENCES C (O a)z20 Wiley et al.: I. of Org. Chem, volume 22, pages S t FCML MCHQ 2044(1957),

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFORMULA
 3. A COMPOUND OF THE FORMULA